The overall goal of the research is to understand the role of the intrinsic cardiac nerves (ICN) in the modulation of cardiac function. The experiments will be performed in chronic, conscious dogs with either normal or denervated (DNV) hearts. The animals will be instrumented to record atrial and ventricular segment/dimensional length changes; atrial and ventricular electrograms; heart rate; and atrioventricular conduction interval. Access of pharmacologic agents will be restricted to the heart by injecting via a chronic, indwelling coronary artery catheter. Direct cholinergic responses of the heart will be assessed with acetylcholine while the cardiac effects of ICN stimulation will be examined using nicotine as an agonist. These responses will also be examined longitudinally to assess post-DNV changes in ICN sensitivity. The relationship of internal variability in cholinergic dose-response curves to plasma levels of stress hormones will be determined. The ability of SP to modulate the direct and reflex responses of the heart to nicotine and veratridine will be examined. Finally, the effects of both stimulation and blockade of the ICN on cardiac responses to adrenergic stimulation and exercise will be employed to ascertain the regulatory capabilities of the ICN in DNV animals. Specifically, we will determine: (1) whether the ICN play a role in the regulation of the heart in chronic, conscious dogs; (2) both the direction and timecourse of changes in the nicotinic sensitivity of the ICN following DNV; (3) the changes in intracardiac chromaffin cell sensitivity after DNV and whether these intrinsic elements take on a larger cardioregulatory role after the heart is separated from the CNS; (4) the role of substance P in the modulation of cardiac neural activity and in the responsiveness of the ICN to pharmacologic activation; (5) the potential for the ICN to alter the responses of the DNV heart to pharmacological and physiological stimulation (i.e., exercise); (6) if "stress" hormones can alter the sensitivity of cholinergic receptors underlying the cardiac responses to the ICN. The information deriving from these experiments will not only help us to understand the role of the ICN in cardiac control but will expand our knowledge of the manner in which the transplanted heart may respond to biologically active substances in the environment. Particularly pertinent to our research is the recognized health hazard of passive or active exposure to cigarette smoke, especially for patients with transplanted (i.e., denervated) hearts. With the advances that have taken place in immunosuppressive therapy, the numbers of these people are increasing. We currently have very little information on the way a heart transplant recipient may respond to the nicotine encountered in the environment. It is highly probable that high enough plasma levels of this almost ubiquitous alkaloid could be attained to produce significant ICN stimulation and its attendant changes in cardiac function.